Transdermal drug delivery (TDD) is the delivery of drugs by absorption through the skin and into the body. TDD has become an established, non-invasive route for both the local and systemic administration of drugs.
TDD offers the advantages of smaller drug doses, improved efficacy, reduced toxicity, elimination of first-pass metabolism, minimization of pain, and possible sustained release.
Despite the obvious advantages of TDD, this delivery approach has not been more widely exploited due to the intrinsic barrier properties of the skin. Human skin is made up of two layers, the epidermis (i.e., the outer layer) and the dermis (i.e., the inner layer). The stratum corneum, which is the outermost layer of the epidermis, acts as the main barrier to drug delivery. With the discovery and implementation of an effective means for penetrating this barrier, TDD becomes a more attractive drug delivery option.
The integrity of the stratum corneum can be disrupted (and hence its permeability increased) through the use of sound energy, electrical energy or physical methods. Considerable effort has been concentrated on identifying non-toxic chemical compounds that will interact with the stratum corneum, thereby increasing the potential for drug penetration. These compounds are sometimes referred to as “permeation enhancers”, “penetration enhancers” or “absorption enhancers”.
A review of the recent patent literature reveals numerous practical examples of permeation enhancers used as transdermal delivery devices, including:
U.S.Pat. No.YearAssigneeTitleEnhancer66994972004AlzaFormulations for thelauryltransdermallactate;administration ofmyristylfenoldopamlactate66389812003EpiCeptTopical compositionsTranscutol ®and methods forPtreating pain65827242003Derma-Dual enhancerTranscutol ®trendscomposition for topicalP; Azone ®and transdermal drugdelivery61567532000VivusLocal administrationAzone ®;of type IIISEPA ®phosphodiesteraseinhibitors for thetreatment of erectiledysfunction61180202000NexMedCrystalline salts ofNexACT ®dodecyl 2-(N,N-di-methylamino)propionate60045781999AlzaPermeation enhancerslaurylfor transdermal drugacetate;delivery compositions,lauryldevices and methodslactate58434681998AlzaSkin permeationglycerolenhancer compositionsmonolaurate;comprising glycerollaurylmonolaurate andacetatelauryl acetate53146941994AlzaTransdermallaurylformulations, methodslactateand devices
Approximately thirty chemical compounds have been routinely used by the pharmaceutical industry as permeation enhancers. Most of these compounds, however, provide only a slight improvement in absorption.
The known and putative permeation enhancers include members of several classes of organic compounds, including:
ClassCompound(s)Alcoholsethanol;isopropanol;benzyl alcoholGlycolspropylene glycol;diethylene glycol monoethylether (Transcutol ®)glycol estersglycerol monolauratefatty acidsoleic acidfatty acid estersisopropyl myristatefatty alcohol esterslauryl lactate;myristyl lactate;cetyl lactate;dodecyl methacrylatemiscellaneousDMSO;laurocapram (Azone ®);2-nonyl-1,3-dioxolane (SEPA ®);dodecyl 2-(N,N-dimethylamino)propionate (NexACT ®)
Most of the permeation enhancers fit a common general structure, which is representative of a non-ionic surface-active agent, i.e., a non-ionic surfactant. The general structure consists of two discrete portions that possess diametrically-opposed physicochemical properties: a polar head and a lipophilic tail. The polar head of the molecule can include one of a variety of functional groups, as listed above; the lipophilic tail consists of a hydrocarbon chain that typically ranges from eight to sixteen carbon atoms in length. FIG. 1 illustrates the structures of eight permeation enhancers (both proprietary and generic) having the aforementioned polar head and lipophilic tail structure.
Of the chemical compounds used as permeation enhancers, one class of compounds in particular—fatty alcohol esters of α-hydroxy carboxylic acids (e.g., alkyl lactates)—has found widespread use in cosmetic and pharmaceutical formulations as humectants and/or emollients. This is particularly true for alkyl lactates where the alkyl group is greater than eight carbon atoms in length (i.e., >C8).
This class of compounds (i.e., fatty alcohol esters of α-hydroxy carboxylic acids)—and specifically dodecyl lactate (also known as lauryl lactate), myristyl lacate and cetyl lactate—has also generated considerable interest for application in TDD due to its permeation enhancing properties.
Esters (including fatty alcohol esters) can be prepared using a variety of traditional techniques. These techniques typically utilize a carboxylic acid (e.g., α-hydroxy carboxylic acid) and alcohol to produce the desired ester.
The following briefly discusses traditional approaches for preparing esters.